Process for preparing benzofuran-2-carboxamide derivatives

ABSTRACT

Provided herein are novel, commercially viable and industrially advantageous processes for the preparation of benzofuran-2-carboxamide derivatives and their intermediates, or a pharmaceutically acceptable salt thereof, in high yield and purity. Provided particularly herein are novel, commercially viable and industrially advantageous processes for the preparation of vilazodone or a pharmaceutically acceptable salt thereof in high yield and purity. Provided also herein is an improved and commercially viable process for the preparation of 3-(4-hydroxybutyl)-1H-indole-5-carbonitrile, in high yield and purity, using novel intermediate compound 3-(4-hydroxybutyryl)-1H-indole-5-carbonitrile.

CROSS REFERENCE TO RELATED APPLICATION

This patent application claims the benefit of priority to IndianProvisional Patent Application No. 2629/CHE/2012, filed on Jul. 2, 2012,which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to novel, commercially viable andindustrially advantageous processes for the preparation ofbenzofuran-2-carboxamide derivatives and their intermediates, or apharmaceutically acceptable salt thereof, in high yield and purity. Thepresent invention particularly relates to novel, commercially viable andindustrially advantageous processes for the preparation of vilazodone ora pharmaceutically acceptable salt thereof in high yield and purity. Thepresent invention further relates to an improved and commercially viableprocess for the preparation of3-(4-hydroxybutyl)-1H-indole-5-carbonitrile, in high yield and purity,using novel intermediate compound3-(4-hydroxybutyryl)-1H-indole-5-carbonitrile.

BACKGROUND OF THE INVENTION

U.S. Pat. No. 5,532,241 (hereinafter referred to as the '241 patent)discloses a variety of piperidine and piperazine derivatives and theirpharmaceutically acceptable salts, processes for their preparation,pharmaceutical compositions comprising the derivatives, and methods ofuse thereof. These compounds are active on the central nervous system,especially in terms of 5-HT_(1A)-agonist and 5-HT-reuptake inhibition.They are furthermore active as serotonin agonists and antagonists. Thesecompounds and their physiologically acceptable acid addition salts can,therefore, be used as active ingredients for anxiolytics,antidepressants, antipsychotics, neuroleptics, and antihypertensives.Among them, Vilazodone hydrochloride,5-[4-[4-(5-Cyanoindol-3-yl)butyl]piperazin-1-yl]benzofuran-2-carboxamidehydrochloride, is a serotonergic antidepressant that is used for thetreatment of major depressive disorder (MDD). Vilazodone hydrochlorideis represented by the following structural formula:

Vilazodone hydrochloride was approved by the FDA for use in the UnitedStates to treat major depressive disorder and it is sold under the tradename VIIBRYD™. It is orally administered as tablets containing 10 mg, 20mg and 40 mg of vilazodone as the hydrochloride salt.

Various processes for the preparation of benzofuran-2-carboxamidederivatives, preferably vilazodone, their intermediate compounds, andtheir pharmaceutically acceptable salts are apparently disclosed in U.S.Pat. No. 5,532,241, U.S. Pat. No. 5,723,614, U.S. Pat. No. 5,977,112,U.S. Pat. No. 5,418,237 and U.S. Pat. No. 7,799,916; U.S. PatentApplication Publication No. 2010/0036139A1; Chinese Patent ApplicationPublication Nos. CN 102267932, CN 102267985, CN 102180868, CN 102796037,CN 102875538, CN 102659660 and CN102617558 and Journal of MedicinalChemistry, 2004, Vol. 47, No. 19, pages 4684-4692; Drugs of the Future2001, 26(3), 247, and Liebigs Ann. Chem. 1988, 749-752.

U.S. Pat. No. 5,532,241 (hereinafter referred to as the '241 patent)describes several synthetic routes for preparing vilazodone. Accordingto one synthetic process, vilazodone is prepared by the condensation of5-(1-pipearzinyl)benzofuran-2-carboxamide with3-(4-chlorobutyl)-1H-indole-5-carbonitrile. According to anothersynthetic process, vilazodone is prepared by reacting5-[4-[4-(5-cyano-1H-indol-3-yl)butyl]piperazin-1-yl]benzofuran-2-carboxylicacid with 2-chloro-1-methylpyridinium methanesulfonate in the presenceof N-methylpyrrolidone to produce a reaction mass, followed by treatmentwith dried ammonia gas and subsequent working up to produce vilazodone.The synthetic routes are depicted in scheme 1:

Similar process for the preparation of vilazodone is also reported inJournal of Medicinal Chemistry, 2004, Vol. 47, No. 19, pages 4684-4692(hereinafter referred to as the ‘JMC article’). As per the processreported in the JMC article (see column-1 of Page No. 4690), thevilazodone is prepared by reacting5-[4-[4-(5-cyano-1H-indol-3-yl)butyl]piperazin-1-yl]benzofuran-2-carboxylicacid with 2-chloro-1-methylpyridinium iodide in the presence ofN-methylpyrrolidone to produce a reaction mass, followed by drop wiseaddition of ethyldiisopropyl amine while introducing ammonia gas andsubsequent work up to produce vilazodone. The resulting vilazodone freebase is then converted into its hydrochloride salt by dissolvingvilazodone free base in hot 2-propanol to form a solution, followed byslow addition of HCl-saturated 2-propanol at room temperature untilcomplete precipitation occurs to yield vilazodone hydrochloride (MeltingPoint: 277-279° C.).

The ‘JMC’ Article also describes a process for the preparation of3-(4-chlorobutyl)-1H-indole-5-carbonitrile as depicted in scheme 2:

As per the process described in the JMC Article,3-(4-chlorobutyl)-1H-indole-5-carbonitrile is prepared by reacting5-cyanoindole with 4-chlorobutyryl chloride in the presence ofisobutyl-AlCl₂ to produce 3-(4-chlorobutyryl)-1H-indole-5-carbonitrile,which is then subjected to selective desoxygenation of the keto functionwith sodium bis(2-methoxyethoxy)aluminum hydride (Vitride/Red-Al) toproduce the 3-(4-chlorobutyl)-1H-indole-5-carbonitrile.

According to U.S. Pat. No. 5,418,237 (hereinafter referred to as the'237 patent) & the Research Article ‘Drugs of the Future 2001, 26(3),247’, 3-(4-chlorobutyl)-1H-indole-5-carbonitrile is prepared by reacting5-cyanoindole with 4-chlorobutyryl chloride to give3-(4-chlorobutyryl)-1H-indole-5-carbonitrile, which then reduced withdiborane to produce the 3-(4-chlorobutyl)-1H-indole-5-carbonitrile.

The processes for the preparation of3-(4-chlorobutyl)-1H-indole-5-carbonitrile described in theaforementioned prior art suffer from disadvantages that the processesinvolve the use of highly dangerous, highly flammable and expensivereducing agents like diborane and bis(2-methoxyethoxy)aluminum hydride(Vitride/Red-Al), which are very difficult to handle at lab scale andcommercial scale operations. Therefore, the use of these reducing agentsis not advisable for scale up operations.

According to U.S. Pat. No. 6,509,475 B1 (hereinafter referred to as the'475 patent), it was not possible to isolate3-(4-chlorobutyl)-1H-indole-5-carbonitrile when Lithium aluminiumhydride (LiAlH₄) or Sodium borohydride with boron trifluoride etherate(NaBH₄/BF₃ ether) is used as a reducing agent for the reduction of3-(4-chlorobutyryl)-1H-indole-5-carbonitrile.

U.S. Pat. No. 5,723,614 (hereinafter referred to as the '614 patent)discloses a process for the preparation of5-(1-pipearzinyl)benzofuran-2-carboxamide. The synthesis is depicted inscheme 3:

According to the '614 patent, the preparation of5-(1-pipearzinyl)benzofuran-2-carboxamide is carried out in four stepsstarting from ethyl 5-aminobenzofuran-2-carboxylate. According to firststep, ethyl 5-(1-piperazinyl)benzofuran-2-carboxylate is prepared byreacting ethyl 5-aminobenzofuran-2-carboxylate withN,N-bis(2-chloroethyl)amine in dichloromethane to produce a reactionmass, followed by customary work-up using a solvent system(isopropanol/water 95:5). According to second step, the ethyl5-(1-piperazinyl)benzofuran-2-carboxylate is subjected to BOC protectionby reacting with di-tert-butyl dicarbonate in tetrahydrofuran to produceethyl 5-(4-tert-butoxycarbonyl-1-piperazinyl)benzofuran-2-caboxylate. Inthird step, the ethyl5-(4-tert-butoxycarbonyl-1-piperazinyl)benzofuran-2-caboxylate isreacted with formamide in the presence of sodium alkoxide inN-methylpyrrolidone to produce5-(4-tert-butoxycarbonyl-1-piperazinyl)benzofuran-2-carboxamide. Infourth step, the5-(4-tert-butoxycarbonyl-1-piperazinyl)benzofuran-2-carboxamide is thendeprotected with methanolic HCl to produce the5-(1-pipearzinyl)benzofuran-2-carboxamide.

Similar process for the preparation of ethyl5-(1-piperazinyl)benzofuran-2-carboxylate is also reported in the JMCarticle. As per the process reported in the JMC article, the ethyl5-(1-piperazinyl)benzofuran-2-carboxylate is prepared by heating asuspension of ethyl 5-aminobenzofuran-2-carboxylate,bis(2-chloroethyl)ammonium chloride and potassium carbonate to refluxtemperature in 1-butanol for 48 hours. The hot suspension is decantedand filtered, followed by evaporation and subsequent recrystallizationof the crude product using methanol to produce the ethyl5-(1-piperazinyl)benzofuran-2-carboxylate as a hydrochloride salt with27% yield.

The processes for the preparation of vilazodone and its intermediatesdescribed in the aforementioned prior art suffer from disadvantages suchas the use of additional and expensive reagents like2-chloro-1-methylpyridinium methanesulfonate,2-chloro-1-methylpyridinium iodide, di-tert-butyl dicarbonate,ethyldiisopropyl amine, formamide and sodium alkoxide; use of expensiveand hazardous solvents like N-methylpyrrolidone, 1-butanol andtetrahydrofuran; use of tedious and cumbersome procedures like multipleprocess steps, prolonged reaction time periods, column chromatographicpurifications, multiple isolations/re-crystallizations, and thusresulting in a poor product yield and quality. Methods involving columnchromatographic purifications are generally undesirable for large-scaleoperations, thereby making the process commercially unfeasible.

CN 102267932 A (hereinafter referred to as CN'932 publication),describes a process for the preparation of vilazodone as depicted inscheme 4:

As per the process described in CN'932 publication, vilazodone isprepared by reacting 3-(4-chlorobutyryl)-1H-indole-5-carbonitrile withsodium borohydride in isopropanol at reflux temperature, followed bytreating the reaction mass with dilute hydrochloric acid and subsequentworkup and then subjecting to column chromatography purifications toproduce 3-(4-hydroxybutyl)-1H-indole-5-carbonitrile. The hydroxylbutylintermediate obtained is then subjected to sulfonylation using asulfonylating agent selected from p-toluenesulfonyl chloride,benzenesulfonyl chloride, methanesulfonyl chloride andtrifluoromethanesulfonyl chloride to produce corresponding sulfonylatedintermediate, which is then condensed with5-(1-piperazinyl)benzofuran-2-carboxamide in acetonitrile to producevilazodone.

The processes for the preparation of vilazodone and its intermediatesdescribed in CN'932 publication suffer from several drawbacks since theprocesses are not reproducible and they involve expensive columnchromatographic purifications, and the yields of vilazodone and itsintermediates obtained are very low. Moreover, the vilazodone and itsintermediates obtained by the processes described in the CN'932publication do not have satisfactory purity.

The present inventors have tried to reproduce the processes exemplifiedin the CN'932 publication. As a result, it has been found that most ofthe reactions described/exemplified in the CN'932 publication do not goto completion. For example, the reaction of3-(4-chlorobutyryl)-1H-indole-5-carbonitrile with sodium borohydride inisopropanol as described in the CN'932 publication (Example 1 in page 8)does not end up with the formation of3-(4-hydroxybutyl)-1H-indole-5-carbonitrile since this reaction ispractically and theoretically impossible. Moreover, it has been observedby the present inventors that the condensation reaction between the3-[4-(p-toluenesulfonyloxy)butyl]-1H-indole-5-carbonitrile and5-(1-piperazinyl)benzofuran-2-carboxamide in acetonitrile exemplified inExample 6 of CN'932 publication does not go to completion even aftermaintenance of prolonged time periods.

U.S. Pat. No. 7,799,916 (hereinafter referred to as U.S. Pat. No. '916patent), describes two processes for the preparation of vilazodone asdepicted in scheme 5:

According to first synthetic route described in U.S. Pat. No. '916patent, vilazodone is prepared by reacting5-bromo-benzofuran-2-carboxamide with3-(4-piperazin-1-ylbutyl)indole-5-carbonitrile in the presence of highlyexpensive reagents including tris(dibenzylidene acetone)dipalladium,tris-tert-butylphosphine, sodium tert-butoxide, and diethylene glycoldimethyl ether to produce a yellow-grey suspension, which is then heatedat 120° C. for 48 hours, followed by cooling the reaction mass to roomtemperature and then subjecting the resulting mass to conventionalworking up to produce vilazodone fee base.

According to another synthetic process described in U.S. Pat. No. '916patent, vilazodone is prepared by reacting3-(4-hydroxybutyl)-1H-indole-5-carbonitrile with sulfurtrioxide/pyridine complex in dimethylsulfoxide to produce a reactionmass, followed by customary work up and then concentrating the resultingmass to produce an oily residue. The resulting residue is thenchromatographed on silica gel using a mixture of dichloromethane andmethyl tert-butyl ether to produce3-(4-oxobutyl)-1H-indole-5-carbonitrile. The oxobutyl compound isreacted with 5-(1-piperazinyl)benzofuran-2-carboxamide in the presenceof sodium cyanoborohydride to produce vilazodone free base, which isfurther treated with aqueous hydrochloric acid to produce vilazodonehydrochloride.

The processes for the preparation of vilazodone and its intermediates asdescribed in the aforementioned prior art suffer from the followingdisadvantages and limitations:

-   a) the prior art processes involve the use of highly flammable and    dangerous reagents like isobutyl-AlCl₂ (DIBAL), sodium    bis(2-methoxyethoxy)aluminum hydride (Vitride/Red-Al), diborane,    Lithium aluminium hydride (LiAlH₄) and boron trifluoride etherate    (NaBH₄/BF₃ ether);-   b) handling of the aforesaid reducing agents is very difficult at    lab scale and in commercial scale operations;-   c) the processes require longer reaction times and the yields and    purity of the product obtained are very low;-   d) the processes involve the use of highly hazardous and expensive    reagents and solvents like 2-chloro-1-methylpyridinium    methanesulfonate, 2-chloro-1-methylpyridinium iodide,    N-methylpyrrolidone, di-tert-butyl dicarbonate, tris(dibenzylidene    acetone)dipalladium, tris-tert-butylphosphine, diethylene glycol    dimethyl ether, sulfur trioxide/pyridine complex and    dimethylsulfoxide;-   e) the processes involve the use of tedious and cumbersome    procedures like prolonged reaction time periods, multiple process    steps, column chromatographic purifications, multiple    isolation/re-crystallizations;-   f) methods involving column chromatographic purifications are    generally undesirable for large-scale operations, thereby making the    process commercially unfeasible;-   g) the overall processes generate a large quantity of chemical waste    which is difficult to treat.

Based on the aforementioned drawbacks, the prior art processes have beenfound to be unsuitable for the preparation of vilazodone and itsintermediates at lab scale and in commercial scale operations.

A need remains for novel, commercially viable and environmentallyfriendly processes of preparing vilazodone and its intermediates withhigh yield and purity, to resolve the problems associated with theprocesses described in the prior art, and that will be suitable forlarge-scale preparation. Desirable process properties includenon-hazardous conditions, environmentally friendly and easy to handlereagents, reduced process steps, reduced reaction time periods, reducedcost, greater simplicity, increased purity, and increased yield of theproduct, thereby enabling the production of vilazodone and itsintermediates in high purity and with high yield.

SUMMARY OF THE INVENTION

The present inventors have surprisingly and unexpectedly found thatbenzofuran-2-carboxamide derivatives such as vilazodone and itsintermediates can be prepared advantageously in high purity and withhigh yield, by amidating substituted or unsubstituted5-(1-piperazinyl)benzofuran-2-carboxylic acid alkyl ester compound withammonia in the presence of an alcohol solvent, preferably methanol. Thenovel process solves the drawbacks associated with the prior processesand is commercially viable for preparing benzofuran-2-carboxamidederivatives.

The present inventors have further surprisingly and unexpectedly foundthat 3-(4-hydroxybutyl)-1H-indole-5-carbonitrile intermediate can beprepared, in high purity and with high yield, by reacting 5-cyanoindolewith 4-chlorobutyryl chloride in the presence of aluminium chloride toproduce an intermediate compound, followed by reacting the compound withan aqueous alcohol to produce3-(4-hydroxybutyryl)-1H-indole-5-carbonitrile, which is then reducedwith sodium cyanoborohydride in the presence of hydrochloric acid andwater in acetonitrile solvent to produce3-(4-hydroxybutyl)-1H-indole-5-carbonitrile.

In one aspect, provided herein is efficient, industrially advantageousand environmentally friendly processes for the preparation of vilazodoneand its key intermediates 5-(1-piperazinyl)benzofuran-2-carboxamide and3-(4-hydroxybutyl)-1H-indole-5-carbonitrile, in high yield and with highpurity, using reduced reaction steps, and without using additional andexpensive reagents and expensive/hazardous solvents.

In another aspect, provided herein is an efficient, industriallyadvantageous and commercially viable process for the preparation of5-(1-piperazinyl)benzofuran-2-carboxylic acid alkyl ester, in high yieldand with high purity, using novel intermediates.

In another aspect, provided herein is a novel intermediate compound,3-(4-hydroxybutyryl)-1H-indole-5-carbonitrile of formula VIII:

or a salt thereof.

The processes for the preparation of vilazodone disclosed herein havethe following advantages over the processes described in the prior art:

-   i) the processes involve the use of novel intermediate compound;-   ii) the overall yield of the vilazodone product is increased and the    purity of the product is increased without additional purifications    such as multiple isolations and column chromatographic    purifications;-   iii) the processes avoid the use of highly inflammable, dangerous    and difficult to handle reagents like DIBAL, sodium    bis(2-methoxyethoxy)aluminum hydride, diborane, Lithium aluminium    hydride and boron trifluoride etherate;-   iv) the overall process involves shorter reactions times and less    expensive reagents thereby making the process cost effective;-   v) the processes avoid the use of additional and excess amounts of    solvents, multiple isolation steps, column chromatographic    purifications;-   vi) the processes avoid the use of expensive and highly hazardous    reagents like 2-chloro-1-methylpyridinium methanesulfonate,    2-chloro-1-methylpyridinium iodide, N-methylpyrrolidone,    di-tert-butyl dicarbonate, tris(dibenzylidene acetone)dipalladium,    tris-tert-butylphosphine, diethylene glycol dimethyl ether, sulfur    trioxide/pyridine complex;-   vii) the processes avoid the use of tedious and cumbersome    procedures like prolonged reaction time periods, higher    temperatures, column chromatographic purifications, multiple    isolations, additional and excess amounts of solvents; and-   viii) the processes involve easy work-up methods and simple    isolation processes, and there is a reduction in chemical waste.

The processes for the preparation of Vilazodone using novel intermediatedisclosed herein may be represented by a schematic diagram as depictedin scheme-6:

Schematic Representation:

DETAILED DESCRIPTION OF THE INVENTION

According to one aspect, there is provided an improved process for thepreparation of a benzofuran-2-carboxamide derivative of formula I:

or a pharmaceutically acceptable salt thereof,wherein R is H, a protecting group ‘P’, or an ‘IND-Q-’ radical,wherein IND is an indol-3-yl radical, a 2,3-di-hydro-1H-indol-3-ylradical, or a 2-oxo-2,3-di-hydro-1H-indol-3-yl radical, which isunsubstituted or mono- or polysubstituted by OH, OA, CN, X, COR₁ orCH₂R₁;Q is selected from —(CH₂)₂—, —(CH₂)₃—, and —(CH₂)₄—;A is an alkyl group having 1 to 6 carbon atoms;X is F, Cl, Br or I;R₁ is OH, OA, NH₂, NHA or NA₂;which comprises:amidation of a benzofuran-2-carboxylic acid ester derivative of formulaII:

or a salt thereof, wherein R is as defined in formula I, and R₂ is analkyl group having 1 to 4 carbon atoms;with ammonia in a suitable solvent to produce thebenzofuran-2-carboxamide compound of formula I, and optionallyconverting the compound of formula I obtained into a pharmaceuticallyacceptable salt thereof, wherein the ammonia is used in the form ofaqueous ammonia or ammonia gas or ammonia saturated in an organicsolvent.

In one embodiment, the compounds of formulae I and II wherein R is H.

In another embodiment, the compounds of formulae I and II wherein R is anitrogen protecting group ‘P’.

Exemplary nitrogen protecting groups ‘P’ include, but are not limitedto, acetyl, pyrrolidinylmethyl, cumyl, benzhydryl, trityl,benzyloxycarbonyl (Cbz), 9-fluorenylmethyloxy carbonyl, benzyloxymethyl,pivaloyloxymethyl (POM), trichloroethxoycarbonyl,1-adamantyloxycarbonyl, allyl, allyloxycarbonyl, trimethylsilyl,tert-butyldimethylsilyl, triethylsilyl, triisopropylsilyl,trimethylsilylethoxymethyl, t-butoxycarbonyl (BOC), t-butyl,1-methyl-1,1-dimethylbenzyl and pivaloyl.

In another embodiment, the compounds of formulae I and II wherein R isan ‘IND-Q-’ radical.

Specifically, the radical IND is an indol-3-yl radical which isunsubstituted or mono- or disubstituted by the radicals indicated; andmost specifically, it is substituted in the 5-position. Specificsubstituents on the indol-3-yl radical are selected from OH, OA, CN,CONH₂, CH₂OH, CO₂H, F, Cl, Br, I, CH₂NH₂, CONHA and CONA₂; and a mostspecific substituent is CN. Specifically, Q is —(CH₂)₄— group. Theradical A is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl,sec-butyl and tert-butyl; and specifically A is methyl or ethyl.

In a preferred embodiment, the compounds of formulae I and II wherein Ris 4-(5-cyanoindol-3-yl)butyl radical.

Specifically, the group R₂ in the compounds of formula II is selectedfrom methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl andtert-butyl; more specifically R₂ is methyl or ethyl; and mostspecifically R₂ is methyl.

In one embodiment, a specific benzofuran-2-carboxamide derivative offormula I prepared by the process described herein is5-(1-pipearzinyl)benzofuran-2-carboxamide of formula I(i) (formula I,wherein R is H):

or a salt thereof.

In another embodiment, a specific benzofuran-2-carboxamide derivative offormula I prepared by the process described herein is vilazodone offormula I(ii) (formula I, wherein R is 4-(5-cyanoindol-3-yl)butylradical):

or a pharmaceutically acceptable salt thereof.

Exemplary pharmaceutically acceptable salts of thebenzofuran-2-carboxamide compound of formula I include, but are notlimited to, hydrochloride, hydrobromide, sulfate, nitrate, phosphate,acetate, propionate, oxalate, succinate, maleate, fumarate,benzenesulfonate, toluenesulfonate, citrate, and tartrate. A specificpharmaceutically acceptable salt of the benzofuran-2-carboxamidecompound of formula I is hydrochloride salt.

Exemplary acid addition salts of the ester compound of formula IIinclude, but are not limited to, hydrochloride, hydrobromide, sulfate,nitrate, phosphate, acetate, propionate, oxalate, succinate, maleate,fumarate, benzenesulfonate, toluenesulfonate, citrate, and tartrate.

Exemplary solvents used in the amidation reaction include, but are notlimited to water, an alcohol, and mixtures thereof.

Specifically, the solvent is selected from the group consisting ofwater, methanol, ethanol, n-propanol, isopropyl alcohol, isobutanol,n-butanol, tert-butanol, and mixtures thereof; more specifically thesolvent is selected from the group consisting of water, methanol,ethanol, isopropyl alcohol, and mixtures thereof; and a most specificsolvent is methanol.

In one embodiment, the organic solvent used for saturating ammonia gasis an alcohol solvent selected from the group as described above.

The reaction temperature and time period for amidation will ordinarilydepend on the starting compound and the solvent employed in thereaction.

In one embodiment, the amidation reaction is carried out at atemperature of about 0° C. to about 50° C., specifically at atemperature of about 5° C. to about 45° C., and more specifically at atemperature of about 25° C. to about 35° C. The reaction time may varyfrom about 1 hour to about 25 hours, and more specifically from about 2hours to about 10 hours.

In another embodiment, the amidation reaction is advantageously carriedout using ammonia gas under pressure of about 1 Kg/Cm² to about 10Kg/Cm², and specifically about 3 Kg/Cm² to about 5 Kg/Cm².

The reaction mass containing the benzofuran-2-carboxamide derivative offormula I obtained may be subjected to usual work up such as a washing,an extraction, an evaporation, a pH adjustment, a layer separation etc.,followed by isolation and/or recrystallization from a suitable solventby conventional methods such as cooling, seeding, partial removal of thesolvent from the solution, by adding an anti-solvent to the solution,evaporation, vacuum distillation, or a combination thereof.

The solvent used for isolating/recrystallizing the purebenzofuran-2-carboxamide derivative of formula I is selected from thegroup consisting of water, acetone, methanol, ethanol, n-propanol,isopropanol, ethyl acetate, dichloromethane, toluene,N,N-dimethyformamide, dimethylsulfoxide, acetonitrile, and mixturesthereof.

The solid obtained is collected by filtration, filtration under vacuum,decantation, centrifugation, filtration employing a filtration media ofa silica gel or celite, or a combination thereof.

The use of ammonia in the presence of a suitable solvent for theamidation reaction disclosed herein allows the product to be easilyisolated and purified, thereby producing a product with high overallyield.

The benzofuran-2-carboxamide derivative of formula I, preferablyvilazodone of formula I(ii), obtained by the process disclosed hereinmay be further dried in, for example, a Vacuum Tray Dryer, a RotoconVacuum Dryer, a Vacuum Paddle Dryer or a pilot plant Rota vapor, tofurther lower residual solvents. Drying can be carried out under reducedpressure until the residual solvent content reduces to the desiredamount such as an amount that is within the limits given by theInternational Conference on Harmonization of Technical Requirements forRegistration of Pharmaceuticals for Human Use (“ICH”) guidelines.

In one embodiment, the drying is carried out at atmospheric pressure orreduced pressures, such as below about 200 mm Hg, or below about 50 mmHg, at temperatures such as about 35° C. to about 90° C. The drying canbe carried out for any desired time period that achieves the desiredresult, such as times about 1 to 20 hours. Drying may also be carriedout for shorter or longer periods of time depending on the productspecifications. Temperatures and pressures will be chosen based on thevolatility of the solvent being used and the foregoing should beconsidered as only a general guidance. Drying can be suitably carriedout in a tray dryer, vacuum oven, air oven, or using a fluidized beddrier, spin flash dryer, flash dryer, and the like.

The benzofuran-2-carboxamide derivative of formula I or apharmaceutically acceptable salt thereof, preferably vilazodone offormula I(ii), obtained by the process disclosed herein has a purity ofgreater than about 98%, specifically greater than about 99%, morespecifically greater than about 99.9%, and most specifically greaterthan about 99.95% as measured by HPLC.

According to another aspect, there is provided an improved process forpreparing an alkyl 5-(1-piperazinyl)benzofuran-2-carboxylate compound offormula II(i):

or an acid addition salt thereof, wherein R₂ is an alkyl group having 1to 4 carbon atoms, comprising:

-   a) reacting an alkyl 5-aminobenzofuran-2-carboxylate compound of    formula III:

-   -   or an acid addition salt thereof, wherein R₂ is as defined in        formula II(i);    -   with a sulfonamide compound of formula IV:

-   -   wherein G is selected from alkyl, cycloalkyl, and a phenyl        radical which is unsubstituted or substituted by alkyl, alkoxy,        halo, nitro, amino or acetyl amino group; in the presence of a        base to produce a sulfonyl piperazine compound of formula V:

-   -   wherein G and R₂ are as defined above; and

-   b) deprotecting the compound of formula V to produce the alkyl    5-(1-piperazinyl)benzofuran-2-carboxylate compound of formula II(i),    and optionally converting the compound of formula II(i) obtained    into an acid addition salt thereof.

Specifically, the group ‘R₂’ in the compounds of formulae II(i), III andV is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl,sec-butyl and tert-butyl; more specifically R₂ is methyl or ethyl; andmost specifically R₂ is methyl.

Except otherwise stated, the term “alkyl” denotes an aliphatichydrocarbon group which may be straight or branched having 1 to 10carbon atoms in the chain, preferably 1 to 6 carbon atoms in the chain;the term “cycloalkyl” denotes a non-aromatic ring system of 3 to 6carbon atoms, preferably of 6 carbon atoms; and the term “alkoxy” refersto an alkoxy group having 1 to 5 carbon atoms, preferably methoxy group.Exemplary alkyl groups include methyl, ethyl, n-propyl, iso-propyl,n-butyl, iso-butyl, t-butyl and n-pentyl. Exemplary cycloalkyl groupsinclude cyclopentyl, cyclohexyl, and the like.

Specifically, the group ‘G’ in the compounds of formulae IV and V isselected from methyl, ethyl, cyclohexyl, phenyl, tolyl, methoxysubstituted phenyl, chloro substituted phenyl and nitro substitutedphenyl; more specifically G is methyl, phenyl or p-tolyl; and mostspecifically G is phenyl.

Unless otherwise specified, the term ‘salt’ as used herein may includeacid addition salts and base addition salts.

Acid addition salts, as used herein, include the salts that are derivedfrom organic and inorganic acids. For example, the acid addition saltsare derived from a therapeutically acceptable acid such as hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, oxalic acid, aceticacid, propionic acid, phosphoric acid, succinic acid, maleic acid,fumaric acid, citric acid, glutaric acid, tartaric acid, benzenesulfonicacid, toluenesulfonic acid, di-p-toluoyl-L-(+)-tartaric acid, malicacid, ascorbic acid, and the like.

Base addition salts may be derived from an organic or an inorganic base.For example, the base addition salts are derived from alkali or alkalineearth metals such as sodium, calcium, potassium and magnesium; ammoniumsalt, organic amines such as ethylamine, tert-butylamine, diethylamine,diisopropylamine, and the like.

In one embodiment, the reaction in step-(a) is carried out at atemperature of about 20° C. to about 100° C. for about 1 hour to about50 hours, specifically at a temperature of about 50° C. to about 90° C.for about 5 hours to about 48 hours, and more specifically at about 70°C. to about 80° C. for about 15 hours to about 45 hours.

The reaction in step-(a) may be carried out in the presence or absenceof a reaction inert solvent. In one embodiment, the base in step-(a) isused as both solvent and acid scavenger.

However, it is also possible to carry out the reaction in step-(a) inthe presence of a reaction inert solvent. Exemplary inert solvents mayinclude, but are not limited to, water, an alcohol, a ketone, achlorinated hydrocarbon solvent, an ester, an ether, a polar aproticsolvent, and mixtures thereof. For example, the inert solvent may beselected from the group consisting of water, methanol, ethanol,n-propanol, isopropyl alcohol, isobutanol, n-butanol, tert-butanol,acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butylketone, methylene chloride, ethylene dichloride, ethyl acetate, methylacetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate,tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, diethyl ether,diisopropyl ether, methyl tert-butyl ether, monoglyme, diglyme,N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, andmixtures thereof.

The base used in step-(a) is an organic or inorganic base, andspecifically an organic base.

Exemplary organic bases include, but are not limited to, trimethylamine,tributylamine, triethylamine, dibutylamine, diisopropylethylamine,N-methylmorpholine, N-ethylmorpholine, 4-(N,N-dimethylamino)pyridine,N,N-dimethylaniline and 1-alkylimidazole.

Exemplary inorganic bases include, but are not limited to, hydroxides,alkoxides, bicarbonates and carbonates of alkali or alkaline earthmetals. Specific inorganic bases are sodium hydroxide, calciumhydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide,sodium carbonate, potassium carbonate, sodium bicarbonate, potassiumbicarbonate, lithium carbonate, sodium tert-butoxide, sodiumisopropoxide and potassium tert-butoxide.

Specifically, the base used in step-(a) is tributylamine ortriethylamine, and most specifically tributylamine.

In one embodiment, the base in step-(a) is used in a ratio of about 1 to20 equivalents, specifically about 5 to 10 equivalents, with respect tothe compound of formula III in order to ensure a proper course of thereaction.

The reaction mass containing the sulfonyl piperazine compound of formulaV obtained in step-(a) may be subjected to usual work up such as awashing, an extraction, a pH adjustment, an evaporation, a layerseparation or a combination thereof. The reaction mass may be useddirectly in the next step to produce the compound of formula II(i), orthe compound of formula V may be isolated and then used in the nextstep.

In one embodiment, the sulfonyl piperazine compound of formula V isisolated from a suitable solvent by conventional methods such ascooling, seeding, partial removal of the solvent from the solution, byadding an anti-solvent to the solution, evaporation, vacuumdistillation, or a combination thereof.

The solvent used to isolate the compound of formula V is selected fromthe group consisting of water, an alcohol, an ether, an ester, ahydrocarbon solvent, a chlorinated hydrocarbon, and mixtures thereof.Specifically, the solvent is selected from the group consisting ofwater, methanol, ethanol, iso-propanol, tetrahydrofuran, 1,4-dioxane,2-methyl-tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether,ethyl acetate, n-pentane, n-hexane, n-heptane, cyclohexane, toluene,xylene, dichloromethane, dichloroethane, chloroform, and mixturesthereof. A most specific solvent is methanol.

In a specific embodiment, the isolation of the compound of formula V iscarried out by cooling the reaction mass, followed by the addition ofmethanol at a temperature of about 25° C. to about 35° C., and morespecifically at a temperature of about 25° C. to about 30° C. Aftercompletion of addition process, the resulting mass is stirred at atemperature of about 25° C. to about 35° C. for at least 10 minutes, andmost specifically at a temperature of about 25° C. to about 30° C. forabout 15 minutes to about 2 hours.

In one embodiment, the deprotection reaction in step-(b) is carried outin the presence of an acid. The acid can be an organic acid or aninorganic acid or a combination thereof.

Specifically, the acid is selected from the group consisting of thehydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, oxalicacid, acetic acid, propionic acid, phosphoric acid, 4-hydroxybenzoicacid, or a combination thereof; more specifically the acid ishydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid,4-hydroxybenzoic acid, or a combination thereof; and a most specificacid is sulfuric acid or hydrobromic acid in acetic acid.

The deprotection reaction in step-(b) may be carried out in the presenceor absence of a reaction inert solvent. In one embodiment, the acidemployed for deprotection is also used as solvent. The reaction inertsolvent may be selected from the group as described above.

In one embodiment, the deprotection reaction in step-(b) is carried outat a temperature of about 20° C. to about 120° C. for at least 5minutes, specifically at a temperature of about 80° C. to about 110° C.for about 10 minutes to about 2 hours, and more specifically at about95° C. to about 105° C. for about 15 minutes to about 1 hour.

In one embodiment, the acid in step-(b) is used in a ratio of about 0.5to 10 equivalents, specifically about 1 to 2.5 equivalents, with respectto the compound of formula V in order to ensure a proper course of thereaction.

The reaction mass containing the alkyl5-(1-piperazinyl)benzofuran-2-carboxylate compound of formula II(i)obtained in step-(b) may be subjected to usual work up such as awashing, an extraction, an evaporation, a pH adjustment, a layerseparation etc., followed by isolation from a suitable solvent by themethods as described hereinabove.

In a specific embodiment, the reaction mass containing the alkyl5-(1-piperazinyl)benzofuran-2-carboxylate compound of formula II(i)obtained in step-(b) is quenched with ice cold water, followed byadjusting the pH of the aqueous layer to a basic value and thenextracting with ethyl acetate and subsequent removal of the solvent bydistillation to produce pure alkyl5-(1-piperazinyl)benzofuran-2-carboxylate compound of formula II(i).

The solid obtained in any of the above process steps may be collected byfiltration, filtration under vacuum, decantation, centrifugation,filtration employing a filtration media of a silica gel or celite, or acombination thereof.

In one embodiment, a specific compound of formula II(i) prepared by theprocess described herein is methyl5-(1-piperazinyl)benzofuran-2-carboxylate of formula II(i)(a) (formulaII(i), wherein R₂ is methyl):

or an acid addition salt thereof.

The use of inexpensive, non-hazardous, readily available and easy tohandle reagents allows the processes disclosed herein to be suitable forthe preparation of vilazodone and its intermediates at lab scale and incommercial scale operations.

Exemplary acid addition salts of the ester compound of formula II(i) andIII include, but are not limited to, hydrochloride, hydrobromide,sulfate, nitrate, phosphate, acetate, propionate, oxalate, succinate,maleate, fumarate, benzenesulfonate, toluenesulfonate, citrate, andtartrate.

According to another aspect, there is provided an improved and costeffective process for the preparation of vilazodone of formula I(ii):

or a pharmaceutically acceptable salt thereof, which comprises:

-   a) reacting 5-cyanoindole of formula IX:

-   -   with 4-chlorobutyryl chloride of formula X:

-   -   in the presence of a Lewis acid in a suitable solvent to produce        a reaction mass;

-   b) isolating the compound from the reaction mass obtained in    step-(a);

-   c) reacting the compound obtained in step-(b) with an alcohol or an    aqueous alcohol to produce    3-(4-hydroxybutyryl)-1H-indole-5-carbonitrile of formula VIII:

-   -   or a salt thereof;

-   d) reducing the hydroxybutyryl compound of formula VIII with a    suitable reducing agent in the presence of an acid to produce    3-(4-hydroxybutyl)-1H-indole-5-carbonitrile of formula VII:

-   -   or a salt thereof;

-   e) converting the hydroxybutyl compound of formula VII obtained in    step-(d) into its sulfonyl ester derivative of formula VI:

-   -   or a salt thereof, wherein R3 is an alkyl, cycloalkyl,        haloalkyl, aralkyl, or a substituted or unsubstituted aryl        group;

-   f) reacting the sulfonyl compound of formula VI with an alkyl    5-(1-piperazinyl)benzofuran-2-carboxylate compound of formula II(i):

-   -   or an acid addition salt thereof, wherein R₂ is an alkyl group        having 1 to 4 carbon atoms, in the presence of a base in a        suitable solvent to produce an alkyl        5-[4-[4-(5-cyanoindol-3-yl)butyl]piperazin-1-yl]benzofuran-2-carboxylate        of formula II(ii):

-   -   or an acid addition salt thereof; and

-   g) amidation of the carboxylate compound of formula II(ii) or an    acid addition salt thereof to produce the vilazodone of formula    I(ii), and optionally converting the vilazodone obtained into a    pharmaceutically acceptable salt thereof.

Unless otherwise specified, the term “alkyl”, as used herein, denotes analiphatic hydrocarbon group which may be straight or branched having 1to 12 carbon atoms in the chain. Preferred alkyl groups have 1 to 4carbon atoms in the chain. The alkyl may be substituted with one or more“cycloalkyl groups”. Exemplary alkyl groups include methyl, ethyl,n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, and n-pentyl.

The term “cycloalkyl”, as used herein, denotes a non-aromatic mono- ormulticyclic ring system of 3 to 10 carbon atoms, preferably of about 5to about 10 carbon atoms. Exemplary monocyclic cycloalkyl groups includecyclopentyl, cyclohexyl, cycloheptyl and the like.

The term “aryl”, as used herein, denotes an aromatic monocyclic ormulticyclic ring system of 6 to 10 carbon atoms. The aryl is optionallysubstituted with one or more “ring system substituents” which may be thesame or different, and are as defined herein. Exemplary aryl groupsinclude phenyl, tolyl or naphthyl.

The term “aralkyl”, as used herein, denotes an aryl-alkyl group whereinthe aryl and alkyl are as herein described. Preferred aralkyls contain alower alkyl moiety. Exemplary aralkyl groups include benzyl, 2-phenethyland naphthalenemethyl.

Specifically, the group ‘R₂’ in the compounds of formulae II(i) andII(ii) is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl,sec-butyl and tert-butyl; more specifically R₂ is methyl or ethyl; andmost specifically R₂ is methyl.

Specifically, the group ‘R3’ in the compound of formula VI is selectedfrom the group consisting of methyl, ethyl, propyl, isopropyl, isobutyl,chloromethyl, fluoromethyl, trifluoromethyl, phenyl, p-tolyl, benzyl,4-nitrophenyl, 4-chlorophenyl, 3-nitrophenyl, 4-chlorobenzyl, and thelike; and most specifically, ‘R3’ is methyl, benzyl, p-tolyl ortrifluoromethyl.

The 3-(4-hydroxybutyryl)-1H-indole-5-carbonitrile of formula VIIIdisclosed herein is novel and constitute another aspect of the presentinvention.

The use of the 3-(4-hydroxybutyryl)-1H-indole-5-carbonitrile of formulaVIII in the preparation of vilazodone of formula I(ii) or apharmaceutical acceptable salt thereof is novel and forms further aspectof the present invention.

Advantageously, the novel intermediate compound of vilazodone disclosedherein is obtained as a solid state form in substantially pure form.

The term “substantially pure” as used herein refers to thehydroxybutyryl compound, disclosed herein, having a purity of greaterthan about 90 wt %, specifically greater than about 95 wt %, morespecifically greater than about 98 wt %, and still more specificallygreater than about 99 wt %. The purity is preferably measured by HighPerformance Liquid Chromatography (HPLC). For example, the purity of thehydroxybutyryl compound obtained by the processes disclosed herein canbe about 95% to about 99%, or about 98% to about 99.9%, as measured byHPLC.

Exemplary Lewis acids used in step-(a) include, but are not limited to,aluminium chloride, calcium chloride, zinc chloride, ferric chloride,and the like. A most specific Lewis acid is aluminium chloride.

In one embodiment, the solvent used in step-(a) is a halogenatedhydrocarbon solvent. Specifically, the halogenated hydrocarbon solventis selected from the group consisting of dichloromethane,dichloroethane, chloroform, carbon tetrachloride, and mixtures thereof;and a most specific halogenated hydrocarbon solvent is dichloromethane.

The reaction temperature and time period will ordinarily depend on thestarting compounds and the solvent/reagent employed in the reaction.

In one embodiment, the reaction in step-(a) is carried out at atemperature of about −10° C. to the reflux temperature of the solventused, specifically at a temperature of about −5° C. to about 50° C., andmore specifically at about 0° C. to about 35° C. The reaction time mayvary between about 1 hour to about 20 hours, specifically about 4 hoursto about 18 hours, and more specifically about 8 hours to about 16hours.

The reaction mass obtained in step-(a) may be subjected to usual work upsuch as a washing, an extraction, a pH adjustment, an evaporation, alayer separation, a decolorization, or a combination thereof.

In one embodiment, the isolation in step-(b) is carried out by cooling,seeding, partial removal of the solvent from the solution, by adding ananti-solvent to the solution, evaporation, vacuum distillation, or acombination thereof.

In another embodiment, the isolation in step-(b) is carried out bypouring the reaction mass into crushed ice with slow stifling and theresulting mixture is stirred at a temperature of about −5° C. to about10° C. for about 20 minutes to about 2 hours, and most specifically at atemperature of about 0° C. to about 5° C. for about 1 hour.

The solid obtained in step-(b) is collected by filtration, filtrationunder vacuum, decantation, centrifugation, filtration employing afiltration media of a silica gel or celite, or a combination thereof.

Exemplary alcohols used in step-(c) include, but are not limited to,methanol, ethanol, isopropanol, n-butanol, and mixtures thereof. A mostspecific alcohol is methanol.

The term “aqueous alcohol” as used herein refers to a solution or mediumcomprising water and an alcohol. Specifically, the ratio of water to thealcohol in the aqueous alcohol solution employed in step-(c) is fromabout 1:10 to about 10:1 (volume/volume), and most specifically about1:1 (volume/volume). A most specific aqueous alcohol is aqueousmethanol.

In one embodiment, the amount of the alcohol or aqueous alcohol employedin step-(c) is about 5 volumes to about 30 volumes, and morespecifically about 15 volumes to about 25 volumes, per gram of thecompound obtained in step-(b).

In one embodiment, the reaction in step-(c) is carried out by heatingthe contents under stifling at a temperature of about 40° C. to thereflux temperature of the alcohol or aqueous alcohol solution used, andmost specifically at the reflux temperature of the alcohol or aqueousalcohol solution used. The reaction time may vary between about 30minutes to about 5 hours, specifically about 1 hour to about 4 hours,and more specifically about 2 hours to about 4 hours.

The reaction mass containing the3-(4-hydroxybutyryl)-1H-indole-5-carbonitrile of formula VIII or a saltthereof obtained in step-(c) may be subjected to usual work up such aswashing, carbon treatment, an extraction, a pH adjustment, anevaporation, a layer separation, decolorization, or a combinationthereof. The reaction mass may be used directly in the next step toproduce the 3-(4-hydroxybutyl)-1H-indole-5-carbonitrile of formula VIIor a salt thereof, or the compound of formula VIII may be isolatedand/or recrystallized and then used in the next step.

In one embodiment, the hydroxybutyryl compound of formula VIII isisolated from a suitable solvent by conventional methods such ascooling, seeding, partial removal of the solvent from the solution, byadding an anti-solvent to the solution, evaporation, vacuumdistillation, or a combination thereof.

The solvent used for isolating the hydroxybutyryl compound of formulaVIII is an aqueous alcohol solvent as described hereinabove.

Exemplary reducing agents used in step-(d) include, but are not limitedto, metal hydrides such as sodium borohydride, sodium cyanoborohydride,and the like. Specifically, the reducing agent used in step-(d) issodium cyanoborohydride.

Exemplary acids used in step-(d) include, but are not limited to,organic acids, inorganic acid, Lewis acids, and mixtures thereof.

In one embodiment, the acid used in step-(d) is selected from the groupconsisting of hydrochloric acid, hydrobromic acid, sulfuric acid, nitricacid, oxalic acid, acetic acid, propionic acid, phosphoric acid,succinic acid, maleic acid, fumaric acid, citric acid, glutaric acid,tartaric acid, benzenesulfonic acid, toluenesulfonic acid, malic acid,ascorbic acid, and the like. Specifically, the acid is hydrochloric acidor hydrobromic acid, and a most specific acid is hydrochloric acid.

For example, hydrochloric acid used may be in the form of concentratedhydrochloric acid, aqueous hydrochloric acid or in the form of hydrogenchloride dissolved in an organic solvent. The organic solvent used fordissolving hydrogen chloride gas or hydrogen chloride is selected fromthe group consisting of ethanol, methanol, isopropyl alcohol, ethylacetate, diethyl ether, dimethyl ether and acetone.

In one embodiment, the reduction in step-(d) is carried out in thepresence of a reaction inert solvent. The term solvent also includesmixture of solvents.

Exemplary reaction inert solvents used in step-(d) include, but are notlimited to, a hydrocarbon solvent, an ether, a nitrile, a halogenatedhydrocarbon solvent, and mixtures thereof.

Specifically, the solvent used in step-(d) is selected from the groupconsisting of n-pentane, n-hexane, n-heptane, cyclohexane, toluene,xylene, tetrahydrofuran, 2-methyl-tetrahydrofuran, dioxane, diethylether, diisopropyl ether, methyl tert-butyl ether, monoglyme, diglyme,acetonitrile, propionitrile, dichloromethane, dichloroethane, andmixtures thereof. A most specific solvent is acetonitrile.

In one embodiment, the reduction in step-(d) is carried out at atemperature of about −10° C. to the reflux temperature of the solventused, specifically at a temperature of about 0° C. to about 40° C., andmore specifically at about 0° C. to about 10° C. The reaction time mayvary between about 10 minutes to about 5 hours, and most specificallyabout 10 minutes to about 2 hours.

The reaction mass containing the3-(4-hydroxybutyl)-1H-indole-5-carbonitrile of formula VII obtained instep-(d) may be subjected to usual work up such as washing, carbontreatment, an extraction, a pH adjustment, an evaporation, a layerseparation, decolorization, or a combination thereof. The reaction massmay be used directly in the next step to produce the sulfonyl compoundof formula VI, or the hydroxybutyl compound of formula VII may beisolated and/or recrystallized and then used in the next step.

In one embodiment, the hydroxybutyl compound of formula VII is isolatedand/or re-crystallized from a suitable solvent by conventional methodssuch as cooling, seeding, partial removal of the solvent from thesolution, by adding an anti-solvent to the solution, evaporation, vacuumdistillation, or a combination thereof.

The solvent used for isolating and/or recrystallizing the hydroxybutylcompound of formula VII is selected from the group consisting ofdichloromethane, dichloroethane, chloroform, and mixtures thereof.

The conversion of the hydroxybutyl compound of formula VII into itssulfonyl ester derivative of formula VI in step-(e) can be carried outby the methods described in the prior art, for example, the processesdescribed in the Chinese Patent Application Publication No. CN 102267932A.

The reaction in step-(f) is carried out in the presence of a suitablereaction inert solvent. Exemplary solvents used in step-(f) include, butare not limited to, a polar aprotic solvent, an alcohol, and mixturesthereof.

Specifically, the solvent used in step-(f) is selected from the groupconsisting of N,N-dimethylformamide, N,N-dimethylacetamide,dimethylsulfoxide, methanol, ethanol, isopropanol, and mixtures thereof.A most specific solvent is N,N-dimethylformamide orN,N-dimethylacetamide.

It has been surprisingly and unexpectedly found that the yield of thealkyl5-[4-[4-(5-cyanoindol-3-yl)butyl]piperazin-1-yl]benzofuran-2-carboxylateof formula II(ii) obtained in step-(f) is significantly increased whenpolar aprotic solvent (preferably N,N-dimethylformamide) is used as asolvent. The present inventors have further observed that whenacetonitrile is used as a solvent in step-(f) the reaction does not goto completion even after maintenance of prolonged time periods.

The base used in step-(f) is an organic or inorganic base selected fromthe group as described hereinabove. Specifically, the base is an organicbase and most specifically triethylamine.

In one embodiment, the reaction in step-(f) is carried out at atemperature of about 0° C. to about the reflux temperature of thesolvent used, specifically at a temperature of about 50° C. to about 90°C., and more specifically at a temperature of about 75° C. to about 85°C. The reaction time may vary from about 20 minutes to about 4 hours,specifically from about 30 minutes to about 2 hours, and morespecifically from about 40 minutes to about 1 hour.

The reaction mass containing the alkyl5-[4-[4-(5-cyanoindol-3-yl)butyl]piperazin-1-yl]benzofuran-2-carboxylateof formula II(ii) obtained in step-(f) may be subjected to usual work upmethods as described hereinabove. The reaction mass may be used directlyin the next step to produce the vilazodone of formula I(ii), or thecarboxylate compound of formula II(ii) may be isolated and/orrecrystallized and then used in the next step. After completion of thereaction, water was added to the reaction mass at a temperature of about20° C. to about 30° C., followed by stifling at the same temperature.

In one embodiment, the carboxylate compound of formula II(ii) isisolated and/or re-crystallized from a suitable solvent by conventionalmethods as described hereinabove.

The solvent used for isolating and/or recrystallizing the carboxylatecompound of formula II(ii) is selected from the group consisting ofwater, an alcohol, a ketone, an ether, an ester, a hydrocarbon solvent,a halogenated hydrocarbon, and mixtures thereof.

In one embodiment, a most specific alkyl5-[4-[4-(5-cyanoindol-3-yl)butyl]piperazin-1-yl]benzofuran-2-carboxylateof formula II(ii) prepared by the process described herein is methyl5-[4-[4-(5-cyanoindol-3-yl)butyl]piperazin-1-yl]benzofuran-2-carboxylateof formula II(ii)(a) (formula II(ii), wherein R₂ is methyl):

or a salt thereof.

In one embodiment, the amidation reaction in step-(g) is advantageouslycarried out using ammonia in a suitable solvent by the methods asdescribed hereinabove. Specifically, the amidation reaction in step-(g)is carried out using ammonia in a solvent selected from the groupconsisting of water, methanol, ethanol, isopropyl alcohol, and mixturesthereof.

In another embodiment, the highly pure vilazodone of formula I(ii)obtained in step-(g) is isolated and/or recrystallized and thencollected by the methods as described hereinabove.

Pharmaceutically acceptable salts of vilazodone, preferably vilazodonehydrochloride, can be prepared in high purity by using the highly purevilazodone, obtained by the processes disclosed herein, by knownmethods.

The vilazodone of formula I(ii) or a pharmaceutically acceptable saltthereof obtained by the process disclosed herein has a purity of greaterthan about 98%, specifically greater than about 99%, more specificallygreater than about 99.9%, and most specifically greater than about99.95% as measured by HPLC.

According to another aspect, there is provided a novel intermediatecompound, 3-(4-hydroxybutyryl)-1H-indole-5-carbonitrile of formula VIII:

or a salt thereof.

According to another aspect, there is provided a process for thepreparation of 3-(4-hydroxybutyryl)-1H-indole-5-carbonitrile of formulaVIII:

or a salt thereof, comprising:

-   a) reacting 5-cyanoindole of formula IX:

-   -   with 4-chlorobutyryl chloride of formula X:

-   -   in the presence of a Lewis acid in a suitable solvent to produce        a reaction mass;

-   b) isolating the compound from the reaction mass obtained in    step-(a); and

-   c) reacting the compound obtained in step-(b) with an alcohol or an    aqueous alcohol to produce    3-(4-hydroxybutyryl)-1H-indole-5-carbonitrile of formula VIII or a    salt thereof.

The above process steps (a, b & c) for the preparation of3-(4-hydroxybutyryl)-1H-indole-5-carbonitrile of formula VIII arecarried out by using the methods, reagents and parameters as describedhereinabove.

According to another aspect, there is provided a process for thepreparation of 3-(4-hydroxybutyl)-1H-indole-5-carbonitrile of formulaVII:

or a salt thereof, comprising:

-   a) reacting 5-cyanoindole of formula IX:

-   -   with 4-chlorobutyryl chloride of formula X:

-   -   in the presence of a Lewis acid in a suitable solvent to produce        a reaction mass;

-   b) isolating the compound from the reaction mass obtained in    step-(a);

-   c) reacting the compound obtained in step-(b) with an alcohol or an    aqueous alcohol to produce    3-(4-hydroxybutyryl)-1H-indole-5-carbonitrile of formula VIII:

-   -   or a salt thereof; and

-   d) reducing the hydroxybutyryl compound of formula VIII with a    suitable reducing agent in the presence of an acid to produce    3-(4-hydroxybutyl)-1H-indole-5-carbonitrile of formula VII or a salt    thereof.

The above process steps (a, b, c & d) for the preparation of3-(4-hydroxybutyl)-1H-indole-5-carbonitrile of formula VII are carriedout by using the methods, reagents and parameters as describedhereinabove.

According to another aspect, there is provided an improved and costeffective process for the preparation of an alkyl5-[4-[4-(5-cyanoindol-3-yl)butyl]piperazin-1-yl]benzofuran-2-carboxylateof formula II(ii):

or an acid addition salt thereof, wherein R₂ is an alkyl group having 1to 4 carbon atoms, which comprises reacting a sulfonyl compound offormula VI:

or a salt thereof, wherein ‘R3’ is an alkyl, cycloalkyl, haloalkyl,aralkyl, or substituted or unsubstituted aryl group; with an alkyl5-(1-piperazinyl)benzofuran-2-carboxylate compound of formula II(i):

or an acid addition salt thereof, wherein R₂ is an alkyl group having 1to 4 carbon atoms; in the presence of a base in a polar aprotic solventto produce the alkyl5-[4-[4-(5-cyanoindol-3-yl)butyl]piperazin-1-yl]benzofuran-2-carboxylateof formula II(ii) or an acid addition salt thereof, wherein the polaraprotic solvent is selected from the group consisting ofN,N-dimethylformamide, N,N-dimethylacetamide and dimethylsulfoxide or acombination thereof.

The above process for the preparation of the alkyl5-[4-[4-(5-cyanoindol-3-yl)butyl]piperazin-1-yl]benzofuran-2-carboxylateof formula II(ii) is carried out by using the methods, reagents andparameters as described hereinabove. In one embodiment, the polaraprotic solvent used is N,N-dimethylformamide.

According to another aspect, there is provided an improved process forthe preparation of 3-(4-chlorobutyl)-1H-indole-5-carbonitrile of formulaXII:

or a salt thereof, comprising reducing3-(4-chlorobutyryl)-1H-indole-5-carbonitrile of formula XIII:

or a salt thereof, with sodium cyanoborohydride or sodium borohydride inthe presence of chlorotrimethylsilane in a suitable solvent to producethe 3-(4-chlorobutyl)-1H-indole-5-carbonitrile of formula XII or a saltthereof.

Exemplary solvents used for reducing the compound of formula XIIIdescribed herein include, but are not limited to, an ether, a nitrile, ahalogenated hydrocarbon solvent, and mixtures thereof.

Specifically, the solvent is selected from the group consisting oftetrahydrofuran, 2-methyl-tetrahydrofuran, dioxane, diethyl ether,diisopropyl ether, methyl tert-butyl ether, monoglyme, diglyme,acetonitrile, propionitrile, dichloromethane, dichloroethane, andmixtures thereof. A most specific solvent is acetonitrile.

In one embodiment, the reduction is carried out at a temperature ofabout −10° C. to the reflux temperature of the solvent used,specifically at a temperature of about 0° C. to about 40° C., and morespecifically at about 0° C. to about 30° C. The reaction time may varybetween about 1 hour to about 20 hours, and most specifically about 6hours to about 16 hours.

The reaction mass containing the3-(4-chlorobutyl)-1H-indole-5-carbonitrile of formula XII obtained maybe subjected to usual work up methods as described hereinabove.

In one embodiment, the 3-(4-chlorobutyl)-1H-indole-5-carbonitrile offormula XII obtained is isolated and/or re-crystallized from a suitablesolvent by conventional methods as described hereinabove.

The solvent used for isolating and/or recrystallizing the3-(4-chlorobutyl)-1H-indole-5-carbonitrile of formula XII is selectedfrom the group consisting of water, methanol, ethanol, isopropanol,dichloromethane, dichloroethane, chloroform, and mixtures thereof.

It has been surprisingly found that the reduction of3-(4-chlorobutyryl)-1H-indole-5-carbonitrile of formula XIII producesthe product with higher yields (above 75%) when sodium cyanoborohydrideor sodium borohydride is used as a reducing agent in the presence ofchlorotrimethylsilane.

Instrumental Details:

Infra-Red Spectroscopy (FT-IR):

FT-IR spectroscopy was carried out with a Bruker vertex 70 spectrometer.For the production of the KBr compacts approximately 5 mg of sample waspowdered with 200 mg of KBr. The spectra were recorded in transmissionmode ranging from 3800 cm⁻¹ to 650 cm⁻¹.

Differential Scanning Calorimetry (DSC):

Differential Scanning calorimetry (DSC) measurements were performed witha Differential Scanning calorimeter (DSC Q200 V23.10 Build 79, UniversalV4.4A TA Instruments) equilibrated at 40° C. and Ramp at a scan rate of10° C. per minute to 210° C.

The following examples are given for the purpose of illustrating thepresent invention and should not be considered as limitation on thescope or spirit of the invention.

EXAMPLES Example 1 Preparation of5-(1-Piperazinyl)benzofuran-2-carboxamide Step-1: Preparation of Methyl5-[4-(Benzenesulfonyl)-1-piperazinyl]benzofuran-2-carboxylate

Methyl 5-aminobenzofuran-2-carboxylate (200 g) andN-benzenesulfonyl-N,N-bis(2-chloroethyl)amine (289 g) were added totributyl amine (1012 ml) under stifling at 25-30° C. The resultingmixture was heated to 73-77° C., followed by stirring for 43 hours atthe same temperature. The reaction mass was cooled to 25-30° C.,followed by the addition of methanol (506 ml) and then stirring for 30minutes at 25-30° C. The resulting mass was filtered, washed withchilled methanol (200 ml) and then dried to produce 220 g of methyl5-[4-(benzenesulfonyl)-1-piperazinyl]benzofuran-2-carboxylate as a finepowder (Purity by HPLC: 99.5%).

Step-2: Preparation of Methyl 5-(1-piperazinyl)benzofuran-2-carboxylate

Method A:

Methyl 5-[4-(benzenesulfonyl)-1-piperazinyl]benzofuran-2-carboxylate (10g) was added to sulfuric acid (25 g) at 25-30° C. and the mixture washeated to 98-102° C., followed by stirring for 15 minutes at the sametemperature. The reaction mass was cooled to 25-30° C. and then pouredinto ice cold water (80 ml). The pH of the resulting aqueous layer wasadjusted to 9-10 with ammonium hydroxide solution, followed byextracting with ethyl acetate (3×200 ml) and then distilling off thesolvent under vacuum to produce 6.5 g of methyl5-(1-piperazinyl)benzofuran-2-carboxylate (Yield: 96%).

Method B:

Methyl 5-[4-(benzenesulfonyl)-1-piperazinyl]benzofuran-2-carboxylate (30g) was added to a solution of hydrobromic acid in acetic acid (180 ml)and 4-hydroxybenzoic acid (24 g). The resulting mixture was stirred for5 minutes at 25-30° C., followed by heating the mixture to 80-85° C. andmaintaining for 6 hours at the same temperature. The reaction mass waspoured into methanolic HCl (1000 ml), followed by heating to reflux andthen stirring for 6 hours under reflux. The resulting mass was cooled to0-5° C. and then stirred for 1 hour at the same temperature. Theseparated solid was filtered and washed with chilled methanol (100 ml).The wet solid was added to methanolic HCl (500 ml) and then heated toreflux for 4 hours. The resulting mass was cooled to 0-5° C. and thenstirred for 1 hour at the same temperature. The separated solid wasfiltered, washed with chilled methanol (100 ml) and then dried at 60-65°C. The resulting solid was added to toluene (500 ml) at 25-30° C.,followed by purging ammonia gas slowly for 7 hours. After completion ofthe ammonia gas purging, the reaction mass was stirred for 15 minutes at25-30° C. The resulting mass was filtered and the filtrate was distilledto produce 16 g of methyl 5-(1-piperazinyl)benzofuran-2-carboxylate(Purity by HPLC: 99.5%; Yield: 82.5%).

Step-3: Preparation of 5-(1-Piperazinyl)benzofuran-2-carboxamide

Methyl 5-(1-piperazinyl)benzofuran-2-carboxylate (37 g) was added tosaturated methanolic ammonia solution (1850 ml) at 25-30° C., themixture was stirred for 6 to 16 hours at the same temperature. Thereaction mass was distilled under vacuum to remove the solvent aftercompletion of the reaction. Water (148 ml) was added to the resultingresidue, followed by adjusting the pH to 2-4 with concentrated HCl andthen filtering the aqueous layer. The pH of the resulting aqueous layerwas adjusted to 9-10 with ammonium hydroxide solution. The separatedsolid was filtered, washed with water (100 ml) and then dried to produce25.5 g of 5-(1-piperazinyl)benzofuran-2-carboxamide (Purity by HPLC:99%; Yield: 73.1%).

Example 2 Preparation of Methyl5-[4-[4-(5-cyanoindol-3-yl)butyl]piperazin-1-yl]benzofuran-2-carboxylateStep-1: Preparation of 3-(4-Hydroxybutyryl)-1H-indole-5-carbonitrile

Aluminium chloride (82.44 g) was added to dichloromethane (350 ml) understifling at 25-30° C. The resulting mass was cooled to 0-5° C., followedby drop-wise addition of 4-chlorobutyryl chloride (87.5 g) for 30-45minutes at 0° C. and then stirring for 5 minutes at the sametemperature. A solution of 5-cyanoindole (50 g) in dichloromethane (350ml) was added drop-wise to the resulting mass at 0-5° C. within 1-2hours, followed by stirring for 30 minutes at the same temperature. Thetemperature of the reaction mass was gradually increased to 25-30° C.,followed by stirring for 12-16 hours at the same temperature. Thereaction mass was slowly poured into crushed ice (420 g) with slowstirring, the resulting mixture was cooled to 0-5° C. and then stirredfor 1 hour at the same temperature. The separated solid was filtered,washed the material subsequently with dichloromethane (2×85 ml) andwater (2×85 ml) and then dried at 25-30° C. to produce a solid material(Dry weight: 93 g). The resulting solid was added to 50% aqueousmethanol (2500 ml) at 25-30° C., followed by heating to reflux andstirring for 2 to 3 hours at reflux. Activated carbon (10 g) was addedto the reaction mass at reflux temperature and then stirred for 5minutes at the same temperature. The resulting mixture was filteredthrough celite bed and washed the bed with hot 50% aqueous methanol (100ml). The resulting filtrate was initially cooled to 25-30° C. andfurther cooled to 0-5° C., followed by maintaining for 1 hour at thesame temperature. The separated solid was filtered, washed with chilled50% aqueous methanol (50 ml) and then dried at 60-65° C. until constantweight to produce 59.5 g of pure3-(4-hydroxybutyryl)-1H-indole-5-carbonitrile as a white crystallinesolid (Purity by HPLC: 99%; Yield: 74.1%).

Analytical Data:

Melting Point: 176° C. (measured by DSC); Infra-red (FT-IR) Data (KBrpellet): 3525 cm⁻¹ (—OH), 3151 cm⁻¹ (—NH), 2861-2957 cm⁻¹ (—CH₂), 2221cm⁻¹ (—CN), 1626 cm⁻¹ (—C═O), 1615 cm⁻¹ (—C═C, Ar); and Mass (m/z): 229(M+1).

Step-2: Preparation of 3-(4-Hydroxybutyl)-1H-indole-5-carbonitrile

3-(4-Hydroxybutyryl)-1H-indole-5-carbonitrile (50 g) was added toacetonitrile (750 ml) at 25-30° C., followed by the addition of sodiumcyanoborohydride (75 g) at the same temperature. The resulting mixturewas cooled to 0-5° C., followed by drop-wise addition of a mixture ofconcentrated HCl (112.5 ml) and water (112.5 ml) for a period of 15minutes at the same temperature. After completion of the reaction, water(750 ml) was added to the reaction mass at 0-5° C., followed by stiflingfor 5 minutes at the same temperature. The layers were separated and theaqueous layer was extracted two times with toluene (2×1000 ml). Theresulting organic layers were combined, washed two times with water(2×1000 ml), and then distilled off the solvent under vacuum to produce42 g of the titled compound as a residue. Dichloromethane (420 ml) wasadded to the residue at 25-30° C. to form a clear solution, followed byfiltration to remove undissolved particles. The resulting filtrate wascooled to −5° C. to 0° C. and then stirred for 1-2 hours at the sametemperature. The separated solid was filtered, washed with chilleddichloromethane (42 ml) and then dried at 50-55° C. to produce 31 g of3-(4-hydroxybutyl)-1H-indole-5-carbonitrile (Purity by HPLC: 99%). Themother liquors were taken and distilled off the solvent under vacuum togive 11 g of the titled compound as a residue (Total yield: 86%).

Step-3: Preparation of3-[4-(p-toluenesulfonyloxy)butyl]-1H-indole-5-carbonitrile

3-[4-(p-Toluenesulfonyloxy)butyl]-1H-indole-5-carbonitrile was preparedby reacting 3-(4-hydroxybutyl)-1H-indole-5-carbonitrile withp-toluenesulfonyl chloride in the presence of base in dichloromethane asper the process exemplified in example 2 of Chinese Patent ApplicationPublication No. CN 102267932 A.

Step-4: Preparation of Methyl5-[4-[4-(5-cyanoindol-3-yl)butyl]piperazin-1-yl]benzofuran-2-carboxylate

Methyl 5-(1-piperazinyl)benzofuran-2-carboxylate (5 g),3-[4-(p-toluenesulfonyloxy) butyl]-1H-indole-5-carbonitrile (6.3 g) andtriethylamine (7 ml) were added to dimethylformamide (6.3 ml) and theresulting mixture was heated to 77-82° C., followed by stirring for 45minutes at the same temperature. Water (30 ml) was added to the reactionmass and then stirred for 5 minutes at 25-30° C. The separated aqueouslayer was extracted two times with toluene (2×250 ml). The resultingorganic layers were combined and then washed two times with water (2×250ml) and then distilled off the solvent under vacuum to produce 9.5 g ofthe titled compound as a residue. Methanol (47.5 ml) was added to theresidue at 25-30° C. and then stirred for 30 minutes at the sametemperature. The separated solid was filtered, washed with chilledmethanol (10 ml) and then dried the material at 70-75° C. to produce 6 gof Methyl5-[4-[4-(5-cyanoindol-3-yl)butyl]piperazin-1-yl]benzofuran-2-carboxylate(Purity by HPLC: 99%; Yield: 76.9%).

Example 3 Preparation of 3-(4-Chlorobutyl)-1H-indole-5-carbonitrileStep-1: Preparation of 3-(4-Chlorobutyryl)-1H-indole-5-carbonitrile

Aluminium chloride (82.44 g) was added to dichloromethane (350 ml) understifling at 25-30° C. The resulting mass was cooled to 0-5° C., followedby drop-wise addition of 4-chlorobutyryl chloride (87.5 g) for 30-45minutes at 0° C. and then stirring for 5 minutes at the sametemperature. A solution of 5-cyanoindole (50 g) in dichloromethane (350ml) was added drop-wise to the resulting mass at 0-5° C. within 1-2hours, followed by stirring for 30 minutes at the same temperature. Thetemperature of the reaction mass was gradually increased to 25-30° C.,followed by stirring for 12-16 hours at the same temperature. Thereaction mass was slowly poured into crushed ice (420 g) with slowstirring, the resulting mixture was cooled to 0-5° C. and then stirredfor 1 hour at the same temperature. The separated solid was filtered,washed the material subsequently with dichloromethane (2×85 ml) andwater (2×85 ml) and then dried at 25-30° C. to produce a solid material(Dry weight: 93 g). The resulting solid was dissolved in ethyl acetate(4000 ml) at 50-55° C., followed by the addition of activated carbon (5g) and then stifling the mixture for 5 minutes at the same temperature.The resulting mass was filtered through celite bed and washed the bedwith hot ethyl acetate (100 ml). The resulting filtrate was initiallycooled to 25-30° C. and further cooled to 0-5° C., followed by stirringthe mass for 1 hour at the same temperature. The separated solid wasfiltered, washed with chilled ethyl acetate (100 ml) and then dried thematerial at 50-55° C. until constant weight to produce 65 g of3-(4-chlorobutyryl)-1H-indole-5-carbonitrile (Purity by HPLC: 99.2%;Yield: 74.8%).

Step-2: Preparation of 3-(4-Chlorobutyl)-1H-indole-5-carbonitrile

Chlorotrimethylsilane (137 g) was added to a mixture of3-(4-chlorobutyryl)-1H-indole-5-carbonitrile (50 g) and acetonitrile(750 ml) at 25-30° C. The resulting mixture was cooled to 0° C.,followed by portion wise addition of sodium cyanoborohydride (75 g)while maintaining the temperature at 0-5° C. during the time period of30 minutes to 1 hour. The resulting mass was stirred for 1 hour at thesame temperature. The temperature of the reaction mass was then raisedto 25-30° C., followed by stifling for 6-16 hours at the sametemperature. The reaction mass was slowly poured into water (5 Lt) at25-30° C. and then stirred for 30 minutes to 1 hour at the sametemperature. The separated solid was filtered and then dissolved indichloromethane (900 ml) and the resulting organic layer was washed with20% sodium chloride solution (400 ml×10). The resulting organic layerwas subjected to carbon treatment, followed by distillation of theorganic layer at 50-55° C. under vacuum to produce the titled compoundas a residue. The resulting residue was dissolved in 5% aqueous methanol(4 to 5 times to the weight of the residue), followed carbon treatmentat 50-55° C. The resulting filtrate was finally cooled to 25-30° C., theseparated solid was filtered, washed with chilled 5% aqueous methanol(50 ml) and then dried the material at 60-65° C. to produce 31 g of3-(4-chlorobutyl)-1H-indole-5-carbonitrile (First Crop). The resultingfiltrate was cooled to 0-5° C. and then stirred for 30 minutes at thesame temperature. The separated solid was filtered, washed with chilled5% aqueous methanol and then dried the material at 60-65° C. to produce10.5 g of the titled compound (Second Crop) (Purity by HPLC: 99.3; Totalyield: 87.2%).

Example 4 Preparation of5-[4-[4-(5-Cyanoindol-3-yl)butyl]piperazin-1-yl]benzofuran-2-carboxamide(Vilazodone)

Methyl5-[4-[4-(5-cyanoindol-3-yl)butyl]piperazin-1-yl]benzofuran-2-carboxylate(41 g) was added to saturated methanolic ammonia solution (8200 ml)under stirring at 25-30° C., the resulting mixture was stirred for 3 to4 hours at the same temperature to form a clear solution. The reactionmass was stirred for 24 hours at 25-30° C., followed by filtration ofthe separated solid and then dried to produce 28 g of vilazodone. Themother liquors were taken and the solvent was distilled off under vacuumuntil the solvent quantity reaches around 1200 ml of the initial volume.The resulting mass was cooled to 25-30° C., followed by filtration andthen drying to produce 11 g of Vilazodone (Purity by HPLC: 99.5%; Yield:98.5%).

Example 5 Preparation of Vilazodone

Methyl5-[4-[4-(5-cyanoindol-3-yl)butyl]piperazin-1-yl]benzofuran-2-carboxylate(41 g) was taken in methanol (1000 ml) under stifling at 25-35° C.,followed by reacting with ammonia gas for 2 hours under pressure of 4Kg/cm². The separated solid was filtered and then dried to produce 32 gof vilazodone. The mother liquors were taken and the solvent wasdistilled off under vacuum until the solvent quantity reaches around 50ml of the initial volume. The resulting mass was cooled to 25-30° C.,followed by filtration and then drying to produce 6 g of Vilazodone(Purity by HPLC: 99.5%; Yield: 96%).

Example 6 Preparation of Vilazodone Hydrochloride

Vilazodone hydrochloride (1 g) was dissolved in methanol (400 ml) at 60°C. and the resulting solution was subjected to carbon treatment bystifling the solution with activated carbon (0.4 g) for 10 minutes at58-62° C. The resulting mixture was filtered through a hyflo bed and theresulting filtrate was cooled to 25-30° C. and then subjected tospray-drying in a mini spray dryer (Buchi model-290) at an inlettemperature of about 78-81° C. and an outlet temperature of about 45-53°C., and flow rate of 16.8 ml/minute using nitrogen gas to produce 0.75 gof amorphous Vilazodone hydrochloride as a white powder (Purity by HPLC:99.73%).

All ranges disclosed herein are inclusive and combinable. While theinvention has been described with reference to a preferred embodiment,it will be understood by those skilled in the art that various changesmay be made and equivalents may be substituted for elements thereofwithout departing from the scope of the invention. In addition, manymodifications may be made to adapt a particular situation or material tothe teachings of the invention without departing from essential scopethereof. Therefore, it is intended that the invention not be limited tothe particular embodiment disclosed as the best mode contemplated forcarrying out this invention, but that the invention will include allembodiments falling within the scope of the appended claims.

We claim:
 1. A process for the preparation of vilazodone of formulaI(ii):

or a pharmaceutically acceptable salt thereof, which comprises: a)reacting 5-cyanoindole of formula IX:

with 4-chlorobutyryl chloride of formula X:

in the presence of a Lewis acid in a suitable solvent to produce areaction mass; b) isolating the compound from the reaction mass obtainedin step-(a); c) reacting the compound obtained in step-(b) with analcohol or an aqueous alcohol to produce3-(4-hydroxybutyryl)-1H-indole-5-carbonitrile of formula VIII:

or a salt thereof; d) reducing the hydroxybutyryl compound of formulaVIII with a suitable reducing agent in the presence of an acid toproduce 3-(4-hydroxybutyl)-1H-indole-5-carbonitrile of formula VII:

or a salt thereof; e) converting the hydroxybutyl compound of formulaVII obtained in step-(d) into its sulfonyl ester derivative of formulaVI:

or a salt thereof, wherein R3 is an alkyl, cycloalkyl, haloalkyl,aralkyl, or a substituted or unsubstituted aryl group; f) reacting thesulfonyl compound of formula VI with an alkyl5-(1-piperazinyl)benzofuran-2-carboxylate compound of formula II(i):

or an acid addition salt thereof, wherein R₂ is an alkyl group having 1to 4 carbon atoms, in the presence of a base in a suitable solvent toproduce an alkyl5-[4-[4-(5-cyanoindol-3-yl)butyl]piperazin-1-yl]benzofuran-2-carboxylateof formula II(ii):

or an acid addition salt thereof, wherein R₂ is as defined above; and g)amidation of the carboxylate compound of formula II(ii) or an acidaddition salt thereof to produce the vilazodone of formula I(ii), andoptionally converting the vilazodone obtained into a pharmaceuticallyacceptable salt thereof.
 2. The process of claim 1, wherein the group‘R₂’ in the compounds of formulae II(i) and II(ii) is selected frommethyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and tert-butyl;and wherein the group ‘R3’ in the compound of formula VI is selectedfrom the group consisting of methyl, ethyl, propyl, isopropyl, isobutyl,chloromethyl, fluoromethyl, trifluoromethyl, phenyl, p-tolyl, benzyl,4-nitrophenyl, 4-chlorophenyl, 3-nitrophenyl and 4-chlorobenzyl.
 3. Theprocess of claim 2, wherein the group ‘R₂’ is methyl or ethyl; andwherein the group ‘R3’ is methyl, benzyl, p-tolyl or trifluoromethyl. 4.The process of claim 1, wherein the Lewis acid used in step-(a) isselected from the group consisting of aluminium chloride, calciumchloride, zinc chloride and ferric chloride; wherein the solvent used instep-(a) is a halogenated hydrocarbon solvent; wherein the isolation instep-(b) is carried out by cooling, seeding, partial removal of thesolvent from the solution, by adding an anti-solvent to the solution,evaporation, vacuum distillation, or a combination thereof; and whereinthe solid obtained in step-(b) is collected by filtration, filtrationunder vacuum, decantation, centrifugation, filtration employing afiltration media of a silica gel or celite, or a combination thereof. 5.The process of claim 4, wherein the Lewis acid used in step-(a) isaluminium chloride; wherein the halogenated hydrocarbon solvent isdichloromethane; and wherein the isolation in step-(b) is carried out bypouring the reaction mass into crushed ice with slow stirring and theresulting mixture is stirred at a temperature of about −5° C. to about10° C. for about 20 minutes to about 2 hours.
 6. The process of claim 1,wherein the alcohol used in step-(c) is selected from the groupconsisting of methanol, ethanol, isopropanol, n-butanol, and mixturesthereof; wherein the ratio of water to the alcohol in the aqueousalcohol solution employed in step-(c) is from about 1:10 to about 10:1(volume/volume); and wherein the reaction in step-(c) is carried out byheating the contents under stirring at a temperature of about 40° C. tothe reflux temperature of the alcohol or aqueous alcohol solution used.7. The process of claim 6, wherein the alcohol is methanol; wherein theaqueous alcohol is aqueous methanol; wherein the ratio of water to thealcohol in the aqueous alcohol solution is about 1:1 (volume/volume);and wherein the reaction in step-(c) is carried out by heating thecontents under stirring at the reflux temperature of the alcohol oraqueous alcohol solution used.
 8. The process of claim 1, wherein thereducing agent used in step-(d) is a metal hydride; wherein the acidused in step-(d) is an organic acid, an inorganic acid, a Lewis acids,or a mixture thereof; and wherein the reduction in step-(d) is carriedout in the presence of a reaction inert solvent selected from the groupconsisting of a hydrocarbon solvent, an ether, a nitrile, a halogenatedhydrocarbon solvent, and mixtures thereof.
 9. The process of claim 8,wherein the reducing agent used in step-(d) is sodium borohydride orsodium cyanoborohydride; wherein the acid used in step-(d) is selectedfrom the group consisting of hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, oxalic acid, acetic acid, propionic acid,phosphoric acid, succinic acid, maleic acid, fumaric acid, citric acid,glutaric acid, tartaric acid, benzenesulfonic acid, toluenesulfonicacid, malic acid, ascorbic acid; and wherein the solvent used instep-(d) is selected from the group consisting of n-pentane, n-hexane,n-heptane, cyclohexane, toluene, xylene, tetrahydrofuran,2-methyl-tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether,methyl tert-butyl ether, monoglyme, diglyme, acetonitrile,propionitrile, dichloromethane, dichloroethane, and mixtures thereof.10. The process of claim 9, wherein the acid is hydrochloric acid; andwherein the solvent used in step-(d) is acetonitrile.
 11. The process ofclaim 1, wherein the reaction in step-(f) is carried out in the presenceof a suitable reaction inert solvent selected from a polar aproticsolvent, an alcohol, and mixtures thereof; wherein the base used instep-(f) is an organic or inorganic base; and wherein the amidationreaction in step-(g) is carried out using ammonia in a suitable solvent.12. The process of claim 11, wherein the solvent used in step-(f) isN,N-dimethylformamide or N,N-dimethylacetamide; wherein the base used instep-(f) is triethylamine; and wherein the amidation reaction instep-(g) is carried out using ammonia in a solvent selected from thegroup consisting of water, methanol, ethanol, isopropyl alcohol, andmixtures thereof.
 13. A process for the preparation of an alkyl5-[4-[4-(5-cyanoindol-3-yl)butyl]piperazin-1-yl]benzofuran-2-carboxylateof formula II(ii):

or an acid addition salt thereof, wherein R₂ is an alkyl group having 1to 4 carbon atoms, which comprises reacting a sulfonyl compound offormula VI:

or a salt thereof, wherein ‘R3’ is an alkyl, cycloalkyl, haloalkyl,aralkyl, or substituted or unsubstituted aryl group; with an alkyl5-(1-piperazinyl)benzofuran-2-carboxylate compound of formula II(i):

or an acid addition salt thereof, wherein R₂ is as defined in formulaII(ii); in the presence of a base in a polar aprotic solvent to producethe alkyl5-[4-[4-(5-cyanoindol-3-yl)butyl]piperazin-1-yl]benzofuran-2-carboxylateof formula II(ii) or an acid addition salt thereof, wherein the polaraprotic solvent is selected from the group consisting ofN,N-dimethylformamide, N,N-dimethylacetamide and dimethylsulfoxide or acombination thereof.
 14. The process of claim 13, wherein the group ‘R₂’in the compounds of formulae II(i) and II(ii) is methyl or ethyl;wherein the group ‘R3’ in the compound of formula VI is methyl, benzyl,p-tolyl or trifluoromethyl; wherein the polar aprotic solvent isN,N-dimethylformamide.